Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/06—Antimigraine agents

Definitions

• the present invention relates to a method of treating migraine in a mammal, including a human, by administering to the mammal eletriptan and a CNS-penetrant NK-1 receptor antagonist (e.g. , a substance P receptor antagonist). It also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier, eletriptan and a CNS-penetrant NK-1 receptor antagonist.
• a CNS-penetrant NK-1 receptor antagonist e.g. , a substance P receptor antagonist
• the present invention relates to a pharmaceutical composition for the treatment of migraine comprising: (a) eletriptan, 3-(1-methyllpyrrolidin-2(R)-yl]methyl)-5-(2-phenylsulphonylethyl)-1H-indole, or a pharmaceutically acceptable salt of eletriptan; (b) a CNS-penetrant NK-1 receptor antagonist or pharmaceutically acceptable salt thereof; and (c) a pharmaceutically acceptable carrier, wherein the active agents "a” and "b” above are present in amounts that render the combination of the two agents effective in treating migraine.
• Eletriptan is a 5HT 1B/1D receptor agonist and has been shown to be highly effective for the treatment of migraine. Eletriptan has also been disclosed for the treatment of hypertension, emesis, depression, anxiety, an eating disorder, obesity, drug abuse, cluster headache, pain chronic paroxysmal hemicrania and a headache associated with a vascular disorder.
• This invention also relates to a method of treating migraine in a mammal, comprising administering to said mammal an antimigraine effective amount of a pharmaceutical composition comprising: (a) eletriptan or a pharmaceutically acceptable salt of eletriptan; (b) a CNS-penetrant NK-1 receptor antagonist or pharmaceutically acceptable salt thereof and (c) a pharmaceutically acceptable carrier, wherein the active agents "a" and "b" above are present in amounts that render the combination of the two agents effective in treating migraine.
• This invention also relates to a method of treating migraine in a mammal, comprising administering to said mammal: (a) eletriptan or a pharmaceuctially acceptable salt of eletriptan: and (b) a CNS-penetrant NK-1 receptor antagonist or a pharmaceutically acceptable salt thereof, wherein the amounts of the two active agents (a) and (b)that are administered are selected so as to render the combination of such two active agents effective in the treatment of migraine.
• NK-1 receptor antagonists that can be used in the methods and pharmaceutical compositions of this invention are compounds of the formula and their pharmaceutically acceptable salts, wherein X 1 is hydrogen, (C 1 -C 10 ) alkoxy optionally substituted with from one to three flourine atoms or (C 1 -C 10 ) alkyl optionally substituted with from one to three fluorine atoms;
• NK-1 receptor antagonists that can be used in the methods and pharmaceutical compositions of this invention are compounds of the formula I, as defined above, with the further proviso that when neither X 1 , X 2 nor X 3 is a fluorinated alkoxy group, at least one of R 1 , R 3 , R 4 , R 5 , R 6 , R 7 and R 13 is an aryl group substituted with a fluorinated alkoxy group.
• Such compounds are hereinafter referred to as "compounds of the formula Ia”.
• NK-1 receptor antagonists that can be used in the methods and pharmaceutical compositions of this invention are compounds of the formula and their pharmaceutically acceptable salts, wherein A is a ring system selected from phenyl, naphthyl, thienyl, quinolinyl and indolinyl, and wherein the side chain containing NR 2 R 3 is attached to a carbon atom of ring system A;
• the fused bicyclic nucleus of compounds of the formula IXb to which W and the -CH 2 NR 2 R 3 sidechain are attached may be, but is not limited to, one of the following groups: benzoxazolyl, benzthiazolyl, benzimidazolyl, benzisoxazolyl, benzoisothiazolyl, indazolyl, indolyl, isoquinolinyl, benzofuryl, benzothienyl, oxindolyl, benzoxazolinonyl, benzthiazolinonyl, benzimidazolinonyl, benzimidazoliniminyl, dihydrobenzothienyl-S,S-dioxide, benztriazolyl, benzthiadiazolyl, benzoxadiazolyl, and quinazolinyl.
• acids that can be used to prepare pharmaceutically acceptable acid addition salts of eletriptan or basic NK-1 antagonists for use in this invention are those that which form non-toxic acid addition salts, i . e ., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [ i .
• the chemical bases that can be used as reagents to prepare the pharmaceutically acceptable base salts of NK-1 antagonists for use in this invention are those which form non-toxic base salts with the acidic compounds of formula I.
• Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium calcium and magnesium, etc.
• NK-1 receptor antagonists that can be used in the method and pharmaceutical compositions of this invention are compounds of the formula and their pharmaceutically acceptable salts, wherein
• NK-1 receptor antagonists that can be used in the methods and pharmaceutical compositions of this invention are compounds of the formula and their pharmaceutically acceptable salts, wherein
• NK-1 antagonists that can be used in the pharmaceutical compositions and methods of this inventions are the following compounds and their pharmaceutically acceptable salts:
• NK-1 receptor antagonists that can be used in the methods and pharmaceutical compositions of this invention include the following compounds and their pharmaceutically acceptable salts:
• NK-1 receptor antagonists examples include the following compounds and their pharmaceutically acceptable salts:
• Preferred embodiments of this invention relate to the above pharmaceutical compositions for the treatment or prevention of migraine, and the above methods of treating or preventing migraine, wherein the NK-1 receptor antagonist, or pharmaceutically acceptable salt thereof, is selected from the following compounds and their pharmaceutically acceptable salts:
• halo as used herein, unless otherwise indicated, includes chloro, fluoro, bromo and iodo.
• alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
• alkoxy includes O-alkyl groups wherein “alkyl” is defined as above.
• one or more substituents includes from one to the maximum number of substituents possible based on the number of available bonding sites.
• antiimigraine effective amount refers to an amount that is effective in treating migraine.
• treating refers to, and includes, reversing, alleviating, inhibiting the progress of, or preventing a disease, disorder or condition, or one or more symptoms thereof; and "treatment” and “therapeutically” refer to the act of treating, as defined above.
• compositions and methods of this invention comprise, or comprise administering NK-1 receptor antagonists of the formulas I through XXI, which may have chiral centers and therefore exist in different enantiomeric forms.
• This invention includes methods and pharmaceutical compositions, as described above, wherein the NK-1 receptor antagonists that are employed are optical isomers tautomers or stereoisomers of the compounds of formulas I through XXI that are defined above, or mixtures thereof.
• This present invention also relates to pharmaceutical compositions and methods comprising, or comprising administering, pharmaceutically acceptable acid addition salts of eletriptan and an NK-1 antagonist.
• pharmaceutically acceptable acid addition salts of the basic NK-1 receptor antagonists and antidepressant and antianxiety agents employed in the compositions and methods of this invention are those which form non-toxic acid addition salts, i .
• salts containing pharmacologically acceptable anions such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [ i . e ., 1,1'-methylene-bis-(2-hydroxy-3- naphthoate)]salts, with such compounds.
• pharmacologically acceptable anions such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate,
• This invention also relates to pharmaceutical compositions and methods comprising, or comprising administering, pharmaceutically acceptable base addition salts of acidic NK-1 receptor antagonists and antidepressant and antianxiety agents.
• the chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of the NK-1 receptor antagonists and antidepressant and antianxiety agents that are employed in the compositions and methods of this invention are those that form non-toxic base salts with such compounds.
• Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations ( e . g ., potassium and sodium) and alkaline earth metal cations ( e . g ., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
• alkali metal cations e .
• the subject invention also relates to pharmaceutical compositions and methods of treatment that employ isotopically-labeled compounds that are identical to those recited in formulas I through XXI, or to other NK-1 receptor antagonists, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes that can be incorporated into the NK-1 receptor antagonists that are employed in the pharmaceutical compositions and methods of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
• NK-1 receptor antagonists employed in the pharmaceutical compositions and methods of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes are within the scope of this invention.
• Certain isotopically-labeled NK-1 receptor antagonists, for example, those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i . e ., 3 H, and carbon-14, i . e ., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
• substitution with heavier isotopes such as deuterium, i . e ., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
• NK-1 receptor antagonists of the formula I can be prepared as described in the following patents and patent applications, all of which are referred to above and incorporated herein by reference in their entirety WO 93/00331, WO 92/21677, WO 92/15585, WO 92/01688, WO 93/06099, WO 91/18899, United States Patent 5,162,339,and United States Patent 5,232,929.
• NK-1 receptor antagonists of the formula Ia ( i .
• NK-1 receptor antagonists of the formula IXa and IXb can be prepared as described in World Patent Application WO 94/13663, published June 23, 1994.
• NK-1 receptor antagonists of the formula XVIII can be prepared as described in World Patent Application WO 97/08144, published March 6, 1997.
• NK-1 receptor antagonists of the formula XIX can be prepared as described in World Patent Application WO 97/03066, published January 30, 1997 and World Patent Application WO 99/25714, published May 27, 1999.
• NK-1 receptor antagonists of the formula XX can be prepared as described in World Patent Application WO 94/20500, published September 15, 1994.
• NK-1 receptor antagonists of the formula XXI can be prepared as described in World Patent Application WO 93/00330, published January 7, 1993.
• NK-1 receptor antagonists that can be used, together with eletriptan or a pharmaceutically acceptable salt of eletriptan, in the pharmaceutical compositions and methods of this invention are those compounds and pharmaceutically acceptable salts described in the following references: European Patent Application EP 499,313, published August 19, 1992; European Patent Application EP 520,555, published December 30, 1992; PCT Patent Application WO 95/16679, published June 22, 1995; European Patent Application EP 522,808, published January 13, 1993, European Patent Application EP 528,495, published February 24, 1993, PCT Patent Application WO 93/14084, published July 22, 1993, PCT Patent Application WO 93/01169, published January 21, 1993, PCT Patent Application WO 93/01165, published January 21, 1993, PCT Patent Application WO 93/01159, published January 21, 1993, PCT Patent Application WO 92/20661, published November 26, 1992, European Patent Application EP 517,589, published December 12, 1992, European Patent Application EP 428,434, published May 22, 1991, and European Patent Application EP 360,390, published March
• Eletriptan and methods of making it are referred to in United States Patent 5,545,644, which issued on August 13, 1996.
• the hydrobromide salt of eletriptan, and methods of preparing it are referred to in Europe Patent application EP 776,323, which was published on June 4, 1997.
• a method of treating emesis using eletriptan is referred to in United States Patent 5,618,834, which issued on April 8, 1997.
• Compositions containing eletriptan hemisulfate and caffeine and their use in the treatment of migraine and other headaches are referred to in World Patent Application PCT/EP98/04176 which was filed on July 1, 1998.
• This invention relates both to methods of treating migraine in which the NK-1 receptor antagonist and eletriptan, or a pharmaceutically acceptable salt of eletriptan, are administered together, as part of the same pharmaceutical composition, as well as to methods in which these two active agents are administered separately as part of an appropriate dose regimen designed to obtain the benefits of the combination therapy.
• the appropriate dose regimen, the amount of each dose administered, and specific intervals between doses of each active agent will depend upon the subject being treated, the emetogen and the severity of the condition.
• the NK-1 receptor antagonist will be administered to an adult human in an amount ranging from about 0.05 to about 1500 mg per day, in single or divided doses, preferably from about 5 to about 200 mg/day, and eletriptan or a pharmaceutically acceptable salt of eletriptan will be administered in an amount ranging from about 0.1 to about 800 mg per day, in single or divided doses, preferably from about 0.1 to about 400 mg/day when administered orally, buccally or parenterally and from about 100 ⁇ g to about 10 mg/day when administered as an aerosol formulation.
• Variations may nevertheless occur depending upon the species of animal being treated and its individual response to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out.
• dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
• NK-1 receptor antagonists their pharmaceutically acceptable salts eletriptan and the pharmaceutically acceptable salts of eletriptan that are employed in the pharmaceutical compositions and methods of this invention are hereinafter also referred to as "therapeutic agent".
• the therapeutic agents can be administered via either the oral or parenteral route.
• Compositions containing both an NK-1 receptor antagonist and eletriptan or a pharmaceutically acceptable salt of eletriptan will generally be administered orally or parenterally daily, in single or divided doses, so that the total amount of each active agent administered falls within the above guidelines.
• the therapeutic agents may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the routes previously indicated, and such administration may be carried out in single or multiple doses. More particularly, the therapeutic agents of this invention can be administered in a wide variety of different dosage forms, i . e ., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, froches, hard candies, suppositories, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc .
• oral pharmaceutical compositions can be suitably sweetened and/or flavored.
• the therapeutic compounds of this invention when administered separately (i . e ., not in the same pharmaceutical composition) are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
• tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
• disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
• lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
• compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
• preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
• the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
• solutions of a therapeutic agent in either sesame or peanut oil or in aqueous propylene glycol may be employed.
• the aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic.
• These aqueous solutions are suitable for intravenous injection purposes.
• the oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
• the NK-1 receptor antagonist and eletriptan may be formulated in a single pharmaceutical composition or alternatively in individual pharmaceutical compositions for simultaneous, separate or sequential use in accordance with the present invention.
• compositions according to the present invention which contain eletriptan and an NK-1 receptor antagonist, as well as the individual pharamaceutical compositions used to deliver any one of these active agents, are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, by inhalation or insufflation or administration by transdermal patches or by buccal cavity absorption wafers.
• the therapeutic agents are mixed with a pharmaceutical carrier, e . g ., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e . g ., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof.
• a pharmaceutical carrier e . g ., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e . g ., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof
• preformulation compositions when referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
• This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.05 to about 500 mg of each of the therapeutic agents of the present invention.
• the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
• the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
• the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
• enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac acetyl alcohol and cellulose acetate.
• liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, peanut oil or soybean oil, as well as elixirs and similar pharmaceutical vehicles.
• Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethyl cellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
• compositions for administration by injection include those comprising the therapeutic agent or agents in association with a surface-active agent (or wetting agent or surfactant) or in the form of an emulsion (as a water-in-oil or oil-in-water emulsion).
• Suitable surface-active agents include, in particular, non-ionic agents, such as polyoxyethylenesorbitans (e.g. , TweenTM 20, 40, 60, 80 or 85) and other sorbitans (e . g ., SpanTM 20, 40, 60, 80 or 85).
• Compositions with a surface-active agent will conveniently comprise between 0.05 and 5% surface-active agent, and preferably between 0.1 and 2.5%. It will be appreciated that other ingredients may be added, for example mannitol or other pharmaceutically acceptable vehicles, if necessary.
• Suitable emulsions may be prepared using commercially available fat emulsions, such as IntralipidTM, Liposyn TM, InfonutrolTM , Lipofundin TM and LipiphysanTM.
• the therapeutic agents may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e . g ., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e . g ., eggs phospholipids, soybean phospholipids or soybean lecithin) and water.
• an oil e . g ., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil
• a phospholipid e . g ., eggs phospholipids, soybean phospholipids or soybean lecithin
• Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%.
• the fat emulsion will preferably comprise fat droplets between 0.1 and 1.0 ⁇ m, particularly 0.1 and 0.5 ⁇ m, and have a pH in the range of 5.5 to 8.0.
• compositions for inhalation or insufflation include, solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents or mixtures thereof, and powders.
• the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above.
• the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
• Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulised by use of inert gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising devise may be attached to a face mask, tent or intermittent positive pressure breathing machine.
• Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
• compositions of the present invention may also be presented for administration in the form of transdermal patches using conventional technology.
• the compositions may also be administered via the buccal cavity using, for example, absorption wafers.
• the present invention further provides a process for the preparation of a pharmaceutical composition comprising an NK-1 receptor antagonist and eletriptan, which process comprises bringing an NK-1 receptor antagonist and eletriptan into association with a pharmaceutically acceptable carrier or excipient.
• the NK-1 receptor antagonist and eletriptan are presented in a ratio which is consistent with the manifestation of the desired effect.
• a suitable dosage level for the NK-1 receptor antagonist is about 0.05 to 1500 mg per day, preferably about 5 to 200 mg per day.
• the compounds may be administered on a regimen of up to 6 times per day, preferably 1 to 4 times per day.
• a suitable oral dosage level for the eletriptan is about 0.5 to 1500 mg per day, preferably about 20 to 200 mg per day.
• the compounds may be administered on a regimen of up to 6 times per day, preferably 1 to 4 times per day.
• NK-1 receptor antagonists include the delivery of the NK-1 receptor antagonist using an oral dosage form or by injection and the delivery of the eletriptan as a conventional tablet, liquid, elixir or suspension.
• 5-HT lD agonists have a systemic mechanism of action. While the rate of headache recurrence with 5-HT 1D agonists is approximately 40% within a 24 hour period, the overall recurrence rate will decrease when a tachykinin antagonist and eletriptan are administered together in the treatment of migraine, since the combination will affect the migraine in two different ways. Firstly, the eletriptan will lessen the signals to the sensory nerves. Secondly, simultaneously, the NK-1 receptor antagonist will block inflammation around blood vessels in sensitive tissues such as the dura mater. Since the pathogenic circle in migraine is influenced by these two major mechanisms, the chances for headache relapse decrease. When a NK-1 receptor antagonist and eletriptan are both used in the treatment of migraine, both mechanisms will be suppressed and the duration of action in the treatment of migraine will therefore be increased.
• the amount of the NK-1 receptor antagonist and eletriptan required for use in the treatment or prevention of migraine will vary not only with the particular compounds or compositions selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the patient's physician or pharmacist.
• the activity of the compounds of the present invention is determined by their ability to inhibit the binding of substance P at its receptor sites in CHO-cells which reveal NK1 receptor or IM-9 cells employing radioactive ligands.
• the substance P antagonist activity of the herein described piperidine compounds is evaluated using the standard assay procedure described by M. A. Cascieri et al ., as reported in The Journal of Immunology , 133, 3260 (1984). This method essentially involves determining the concentration of the individual compound required to reduce by 50% the amount of radiolabelled substance P ligands at their receptor sites in said isolated cow tissues or IM-9 cells, thereby affording characteristic IC 50 values for each compound tested.
• inhibition of [ 3 H]SP binding to human IM-9 cells by compounds is determined in assay buffer (50 mM Tris-HCl (ph 7.4), 1mM MnCl 2 , 0.02% bovine serum albumin, bacitracin (40 ⁇ g/ml) leupeptin (4 ⁇ g/ml), chymostatin (2 ⁇ g/ml) and phosphoramidon (30 ⁇ g/ml).
• assay buffer 50 mM Tris-HCl (ph 7.4), 1mM MnCl 2 , 0.02% bovine serum albumin, bacitracin (40 ⁇ g/ml) leupeptin (4 ⁇ g/ml), chymostatin (2 ⁇ g/ml) and phosphoramidon (30 ⁇ g/ml).
• the reaction is initiated by the addition of cells to the assay buffer containing 0.56 nM [ 3 H]SP and various concentrations of compounds (total volume; 0.5 ml) and allowed to incubate
• Incubation is terminated by filtration onto GF/B filters (presoaked in 0.1% polyethylenimine for 2 hours). Nonspecific binding is defined as the radioactivity remaining in the presence of 1 ⁇ M SP.
• the filters are placed into tubes and counted using a liquid scintillation counter.
• Compounds and salts can be evaluated as antimigraine agents by testing the extent to which they mimic sumatriptan in contracting the dog isolated saphenous vein strip (P.P.A. Humphrey et al. , Br. J. Pharmacol., 1988; 94: 1128.). This effect can be blocked by methiothepin, a known serotonin antagonist.
• Sumatriptan is known to be useful in the treatment of migraine and produces a selective increase in carotid vascular resistance in the anaesthetized dog. It has been suggested that this is the basis of its efficacy by Fenwick et al. , Br. J. Pharmacol. , 1989; 96: 83.
• formulations may be prepared with separate active ingredients or with a combination of active ingredients in one composition.
• the ratio of NK-1 antagonist to eletriptan will depend upon the choice of active ingredients.
• NK-1 antagonist 5.0 15.0 50.0 5.0 15.0 50.0 5.0 15.0 50.0 5.0 15.0 50.0 Eletriptan 20.0 20.0 40.0 40.0 40.0 80.0 80.0 80.0 80.0 Microcrystalline cellulose 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 Modified food corn starch 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 Lactose 52.5 47.5 34.5 29.5 29.5 29.5 29.5 29.5 29.5 29.5 29.5 Magnesium Stearate 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5
• the active ingredients, cellulose, lactose and a portion of the corn starch are mixed and granulated with 10% corn starch paste.
• the resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate.
• the resulting granulation is then compressed into tablets containing 2.0 mg, 20.0 mg, 26.0 mg, 40.0 mg and 100 mg of the NK-1 receptor antagonist and 5.0 mg or 10.0 mg of eletriptan per tablet.

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